Cyanobenzenesulfenyl halide and process for preparation of 3-substituted benzisothiazole using the same

ABSTRACT

The present invention provides a compound represented by the general formula (I): ##STR1## wherein X represents Cl or Br, a process for preparation of the same and a process for preparation of 3-substituted benzisothiazole by reaction of the compound (I) with a piperazine compound.

FIELD OF THE INVENTION

The present invention relates to novel 2-cyanobenzenesulfenyl halide anda process for preparation of the same, as well as a novel process forpreparation of 3-substituted benzisothiazole using the same compound.2-Cyanobenzenesulfenyl halide is a novel compound which has not beenpreviously known, and is a useful compound, in particular, as anintermediate upon preparation of a 3-substituted benzisothiazolederivative important as an intermediate for preparation ofpharmaceuticals.

BACKGROUND OF THE INVENTION

Hitherto, as a process for preparation of 3-substituted benzisothiazolederivatives, there have been known a number of processes by reacting3-halo-1,2-benzisothiazole with a piperazine compound according to thefollowing Reaction Scheme: ##STR2## See JP-A 63-83067; JP-A 63-83085;EP-A 196096; J. Chem. Soc., Perkin. Trans., 1(8), 2141, 1988; Ger.Offen., 3530089; J. Med. Chem., 29(3), 359, 1986; J. Org. Chem., 43(8),1604, 1978.

OBJECTS OF THE INVENTION

However, 3-halo-1,2-benzisothiazole used in the above known processes asa raw material is not easily available. A method for chlorinating1,2-benzisothiazol-3-one and a method using thiosalicylic acid as astarting material are described in the above references. However, thesemethods use an expensive raw material, have the lower yield and,therefore, they are not said to be industrially advantageous.

As described above, it was difficult to advantageously prepare3-substituted benzisothiazole derivatives on the industrial scale.

Accordingly, one object of the present invention is to provide anindustrially advantageous process for preparation of 3-substitutedbenzisothiazole derivatives.

Another object of the present invention is to provide a usefulintermediate which can be used upon preparation of a 3-substitutedbenzisothiazole derivative.

Still another object of the present invention is to provide a processfor preparation of the above intermediate.

Theses objects as well as other objects and advantages of the presentinvention will become apparent to those skilled in the art from thefollowing description.

SUMMARY OF THE INVENTION

In view of the above circumstances, the present inventors studied hardin order to provide an industrially advantageous process which canprepare a 3-substituted benzisothiazole derivative easily andeconomically without the use of expensive raw materials. As the result,we found that 2-cyanobenzenesulfenyl halide represented by the formula(I) below can be an important intermediate for preparation of a3-substituted benzisothiazole derivative, investigated the physicalproperties of the halide and studied hard to provide an industriallyadvantageous and easy process for preparation of the halide and the3-substituted benzisothiazole derivative.

2-Cyanobenzenesulfenyl halide is a novel compound which has never beendescribed in the literature and the physical properties thereof and aprocess for preparation of the same are not known.

That is, the present inventors found that the present novel2-cyanobenzenesulfenyl halide can be easily obtained by halogenating a2-cyanophenylthio derivative represented by the general formula (II)below, and a 3-substituted benzisothiazole derivative can be easilyobtained by reacting the 2-cyanobenzenesulfenyl halide with a piperazinecompound.

Further, the present inventors found that 3-substituted benzisothiazolederivative can be effectively obtained by a process by successivelyperforming the above two reactions, that is, by halogenating a2-cyanophenylthio derivative to obtain 2-cyanobenzenesulfenyl halidewhich is subsequently reacted with a piperazine compound.

The present invention provides:

(1) 2-cyanobenzenesulfenyl halide represented by the general formula(I): ##STR3## wherein X represents Cl or Br,

(2) a process for preparation of 2-cyanobenzenesulfenyl haliderepresented by the general formula (I) which comprises halogenating a2-cyanophenylthio derivative represented by the general formula (II):##STR4## wherein R₁ represents H, alkaline metal, 2-cyanophenylthiogroup or straight or branched alkyl group having 1 to 4 carbon atoms,

(3) a process for preparation of 3-substituted benzisothiazolerepresented by the general formula (IV): ##STR5## wherein R₂ representsH, alkyl group having 1 to 6 carbon atoms or substituted alkylene grouphaving 1 to 6 carbon atoms, which comprises reacting2-cyanobenzenesulfenyl halide represented by the general formula (I)with a piperazine compound represented by the general formula (III):##STR6## wherein R₂ is as defined in the general formula IV, and

(4) a process for preparation of 3-substituted benzisothiazolerepresented by the general formula (IV) which comprises halogenating a2-cyanophenylthio derivative represented by the general formula (II) toobtain 2-cyanobenzenesulfenyl halide represented by the general formula(I), then reacting the halide represented by the general formula (I)with a piperazine compound represented by the general formula (III).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail below.

In a novel compound, 2-cyanobenzenesulfenyl halide represented by thegeneral formula (I), a group represented by X is Cl or Br. That is, thecompound represented by the general formula (I) is2-cyanobenzenesulfenyl chloride or 2-cyanobenzenesulfenyl bromide.

The compound represented by the general formula (I) can be prepared byhalogenating a 2-cyanophenylthio derivative represented by the generalformula (II).

Group R₁ in the compound represented by the general formula (II) is H,alkaline metal such as sodium, potassium and the like, 2-cyanophenylthiogroup, straight or branched alkyl group having 1 to 4 carbon atoms suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like.The particular compounds represented by the general formula (II) are2-cyanobenzenethiol, 2,2'-dicyanodiphenyl disulfide, 2-cyanophenylmethyl sulfide, 2-cyanophenyl ethyl sulfide, 2-cyanophenyl n-propylsulfide, 2-cyanophenyl isopropyl sulfide, 2-cyanophenyl n-butyl sulfide,2-cyanophenyl t-butyl sulfide and the like.

For halogenating the compound represented by the general formula (II),chlorine, sulfuryl chloride, bromine, sulfuryl bromide, and a mixturethereof can be used as a halogenating agent. Among them, chlorine andbromine are preferable. An amount of a halogenating agent to be usedvaries depending upon a kind of the compound represented by the generalformula (II) and is usually in a range of 0.5 to 7-fold in mole termsrelative to the compound represented by the general formula (II).

A reaction temperature for halogenation varies depending upon a kind ofthe compound represented by the general formula (II) and is usually in arange of about -10° C. to about 160° C., preferably about -5° C. toabout 130° C. When a reaction temperature is too low, the reaction ratebecomes slow. On the other hand, when a reaction temperature is toohigh, side reactions occur, which leads to the decreased yield.

The halogenating reaction can be carried out without any solvent or in asolvent. Examples of the solvent are, not limited to, hydrocarbon suchas hexane, cyclohexane, heptane and the like, halogenated hydrocarbonsuch as dichloroethane, dichloromethane, chloroform and the like,aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene,dichlorobenzene, trichlorobenzene and the like, polar solvent such asN,N-dimethylformamide, dimethyl sulfoxide and the like. When a solventis used, an amount of the solvent to be used is usually, not limited to,0.1 to 10-fold in weight terms relative to the compound represented bythe general formula (II).

2-Cyanobenzenesulfenyl halide, thus obtained, represented by the generalformula (I) can be isolated by the conventional method such asdistillation, crystallization or the like.

2-Cyanobenzenesulfenyl halide, thus obtained, represented by the generalformula (I) can be reacted with a piperazine compound represented by thegeneral formula (III) to obtain 3-substituted benzisothiazolerepresented by the general formula (IV).

Examples of the piperazine compound are piperazine, 1-alkyl-piperazinesuch as 1-methyl-piperazine, 1-ethyl-piperazine, 1-n-butyl-piperazineand the like, and 1-substituted alkylene-piperazine such as1-imidobutylene-piperazine, 1-amidobutylene-piperazine,1-((5-indole)ethylene)-piperazine and the like.

An amount of the piperazine compound to be used is usually in a range of1 to 10-fold, preferably 3 to 6-fold in mole terms relative to2-cyanobenzenesulfenyl halide represented by the general formula (I).

A reaction temperature is usually in a range of about 80° C. to about150° C., preferably about 100° C. to about 130° C. When a reactiontemperature is too low, the reaction rate becomes slow. On the otherhand, when a reaction temperature is too high, side reactions occur,which leads to the decreased yield.

A solvent is not necessarily required and a reaction is preferablycarried out without a solvent. Alternatively, the reaction may becarried out in a solvent. Examples of the solvent are hydrocarbon suchas cyclohexane, heptane and the like, aromatic hydrocarbon such asbenzene, toluene, xylene, chlorobenzene, dichlorobenzene,trichlorobenzene and the like, and polar solvent such asN,N-dimethylformamide, dimethyl sulfoxide and the like. When a solventis used, an amount of the solvent to be used is usually, not to limitedto, in a range of 0.1 to 10-fold in weight terms relative to thecompound represented by the general formula (I).

3-Substituted benzisothiazole, thus obtained, represented by the generalformula (IV) can be isolated from a reaction mixture and purified by theconventional method such as crystallization or the like.

Examples of the particular 3-substituted benzoisothiazole are3-(1-piperazinyl)-1,2-benzisothiazole,3-(4-ethyl-1-piperazinyl)-1,2-benzisothiazole,3-(4-n-butyl-1-piperazinyl)-1,2-benzisothiazole,3-(4-cyclohexyl-1-piperazinyl)-1,2-benzisothiazole and the like. Thesecompounds can be isolated as a mineral acid salt such as hydrochloride,sulfate or the like under acidic conditions in the presence ofhydrochloric acid, sulfuric acid or the like.

3-Substituted benzisothiazole represented by the general formula (IV)can also be prepared by a process where the above two reactions aresuccessively carried out in series, that is, by halogenating2-cyanophenylthio halide represented by the general formula (II) toobtain 2-cyanobenzenesulfenyl halide represented by the general formula(I) which is subsequently reacted with a piperazine compound representedby the general formula (III).

An halogenating reaction and a reaction with the piperazine compound inthis process can be carried out as described for each reaction.

A compound represented by the general formula (II) used as a rawmaterial for preparation of a compound represented by the generalformula (I) can be easily obtained according to a present inventor'sprocess described in Japanese patent application No. 6-289763. That is,2-cyanochlorobenzene is converted into 2-cyanophenyl methyl sulfide witha sodium salt of methylmercaptane, then the methyl group thereof ishalogenated and hydrolyzed to obtain 2-cyanobenzenethiol, which isfurther treated with an alkali to obtain an alkaline metal salt thereof,which is oxidized to obtain 2,2'-dicyanodiphenyl disulfide.

The following Examples illustrate the present invention in detail butare not to be construed to limit the scope thereof.

EXAMPLE 1

67.5 g (0.500 mol) of 2-cyanobenzenethiol and 150 g of chlorobenzenewere placed in a 300 ml four-neck flask equipped with a stirrer, athermometer, a chlorine blowing inlet and a condenser and 39 g (0.55mol) of chlorine was blown therein at about 80° C. over 2 hours whilestirring. The solvent was distilled, followed by evaporation underreduced pressure to obtain 81.7 g of white crystals, which wereidentified to be 2-cyanobenzenesulfenyl chloride from the followingdata. The yield starting from 2-cyanobenzenethiol was 96.4%.

Physical properties

2-Cyanobenzenesulfenyl chloride Appearances: white crystals Meltingpoint: 38.5°-39.0° C. NMR: δ (ppm) 7.37-8.09 (m) IR: (KBr, cm⁻¹) 1595,1467, 1248, 1012, 760

Elementary analysis: Calculated C:49.56;H:2.38;N:8.26;S:18.90 FoundC:49.60;H:2.34;N:8.25;S:18.88

EXAMPLE 2

67.2 g (0.250 mol) of 2,2'-dicyanodiphenyl disulfide and 150 g ofchlorobenzene were placed in a 300 ml four-neck flask equipped with astirrer, a thermometer, a dropping funnel and a condenser and 84.0 g(0.525 mol) of bromine was added dropwise at about 80° C. over one hourwhile stirring. The excess bromine was removed with an aqueous sodiumcarbonate solution, followed by crystallization with cyclohexane toobtain 101.9 g of white crystals, which were identified to be2-cyanobenzenesulfenyl bromide from the following data. The yieldstarting from 2,2'-dicyanodiphenyl disulfide was 95.2%.

Physical properties

2-Cyanobenzenesulfenyl bromide Appearances: white crystals Meltingpoint: 59.5°-60.5° C. NMR: δ (ppm) 7.38-8.07 (m) IR: (KBr, cm⁻¹) 1589,1462, 1242, 958, 760

Elementary analysis: Calculated C:39.27;H:1.88;N:6.54;S:14.98 FoundC:39.32;H:1.88;N:6.52;S:15.00

EXAMPLE 3

74.5 g (0.500 mol) of 2-cyanophenyl methyl sulfide and 250 g ofchlorobenzene were placed in a 500 ml four-neck flask equipped with astirrer, a thermometer, a dropping funnel and a condenser and 96.0 g(0.600 mol) of bromine was added dropwise thereto at about 100° C. overfive hours while stirring. The excess bromine was removed with anaqueous sodium carbonate solution, followed by distillation underreduced pressure to obtain 90.4 g of 2-cyanobenzenesulfenyl bromide. Theyield starting from 2-cyanophenyl methyl sulfide was 84.5%.

EXAMPLE 4

86.2 g (1.00 mol) of piperazine and 7.5 g of chlorobenzene were placedin a 500 ml four-neck flask equipped with a stirrer, a thermometer, adropping funnel and a condenser and 42.4 g (0.25 mol) of molten2-cyanobenzenesulfenyl chloride was added dropwise thereto at about 130°C. over one hour while stirring, followed by stirring for four hours tocomplete the reaction. The excess piperazine was removed with water,followed by acidification with hydrochloric acid and extraction into theaqueous layer. The aqueous layer was basified with an aqueous sodiumhydroxide solution to obtain 40.9 g (m.p.: 89°-90° C.) of3-(1-piperazinyl)-1,2-benzisothiazole as crystals. The yield startingfrom 2-cyanobenzenesulfenyl chloride was 74.7%.

EXAMPLE 5

The same manner as that in Example 4 except for the use of2-cyanobenzenesulfenyl bromide in stead of 2-cyanobenzenesulfenylchloride as a raw material afforded, after cooling of an aqueoussolution acidified with hydrochloric acid, 46.6 g of3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride as crystals(decomposition temperature 275°-280° C.). The yield starting from2-cyanobenzenesulfenyl chloride was 73.0%.

EXAMPLE 6

74.5 g (0.500 mol) of 2-cyanophenyl methyl sulfide and 250 g ofchlorobenzene were placed in a 500 ml four-neck flask equipped with astirrer, a thermometer, a dropping funnel and a condenser and 96.0 g(0.600 mol) of bromine was added dropwise thereto at about 100° C. overfive hours while stirring, followed by stirring for two hours tocomplete the reaction. The excess bromine was removed with an aqueoussodium carbonate solution and the solvent was distilled off to obtain92.0 g of crude 2-cyanobenzenesulfenyl bromide. Separately, 172.4 g(2.00 mol) of piperazine and 15 g of chlorobenzene were placed in a 1000ml four-neck flask equipped with a stirrer, a thermometer, a droppingfunnel and a condenser and the molten crude 2-cyanobenzenesulfenylbromide obtained above was added dropwise thereto at about 130° C. overone hour while stirring, followed by stirring for five hours to completethe reaction. The excess piperazine was removed with water and reactionmixture was acidified with hydrochloric acid, followed by extractioninto an aqueous layer. The aqueous layer was basified with an aqueoussodium hydroxide solution to obtain 65.9 g of3-(1-piperazinyl)-1,2-benzisothiazole as crystals. The yield startingfrom 2-cyanophenyl methyl sulfide was 60.2%.

EXAMPLE 7

The same manner as that in Example 5 except for the use of 100 g (1.00mol) of N-methylpiperazine in stead of piperazine afforded 55.9 g of3-(4-methyl-1-piperazinyl)-1,2-benzisothiazole hydrochloride ascrystals, m.p.: 250°-252° C. The yield starting from2-cyanobenzenesulfenyl bromide was 83.0%.

As described above, according to the present invention, there isprovided a novel 2-cyanobenzenesulfenyl halide and a process forpreparation of the same, and by using the compound, a 3-substitutedbenzisothiazole derivative important as an intermediate for preparationof pharmaceuticals can be industrially prepared advantageously,effectively and economically.

What is claimed is:
 1. 2-Cyanobenzenesulfenyl halide represented by thegeneral formula (I): ##STR7## wherein X represents Cl or Br.
 2. Thecompound according to claim 1, which is 2-cyanobenzenesulfenyl chloride.3. The compound according to claim 1, which is 2-cyanobenzenesulfenylbromide.
 4. A process for preparation of 2-cyanobenzenesulfenyl haliderepresented by the general formula (I), which comprises halogenating a2-cyanophenylthio derivative represented by the general formula (II):##STR8## wherein R₁ represents H, alkaline metal, 2-cyanophenylthiogroup or straight or branched alkyl group having 1 to 4 carbon atoms. 5.The process according to claim 4, wherein halogenation is carried outusing chlorine or bromine.
 6. The process according to claim 4, whereinthe 2-cyanophenylthio derivative is 2-cyanobenzenethiol.
 7. The processaccording to claim 4, wherein the 2-cyanophenylthio derivative is2,2'-dicyanodiphenyl disulfide.
 8. The process according to claim 4,wherein the 2-cyanophenylthio derivative is 2-cyanophenyl methylsulfide.
 9. The process according to claim 4, wherein the2-cyanophenylthio derivative is 2-cyanophenyl t-butyl sulfide.